The hair follicle has emerged as an important focus of research not only because of the psychological and emotional impacts of hair loss or excessive hair growth, but also because the hair follicle is periodically regenerated from a resident stem cell population in the adult and this serves an important model system in stem cell biology, regenerative medicine, and organogenesis. The hair follicle is composed of two principle components, (1)an epithelial population that comprises the majority of the follicle and gives rise to the differentiated cells that form the hair shaft and its surrounding cell layers in the follicl, and (2) a specialized mesenchymal population, the dermal papilla, that guides the activities of these epithelial cells. We have developed methods to manipulate gene expression specifically in the dermal papilla of the hair follicles after they have formed and exploited these to study the signaling between the dermal papilla and the follicular epithelium. This has provided insight onto signals that impinge on DP cells to control the production of signals that in turn regulate keratinocyte behavior and hair growth. These experiments suggest a second mechanism dictating the size and shape of the hair produced that occurs through active and dynamic regulation of the number of DP cells per follicle. The size of the hair correlates with the number of DP cells /follicle. One aim of this research is to test the significance of this correlation by selectively ablating DP cells in adult hair follicles and evaluating both the effects on hair growt and cycling as well as mechanisms that may compensate for cell death in the DP compartment. A second is to characterize the role of a transcription factor, Sox2 that is expressed in the DP. The phenotypes we observe after deleting the Sox2 gene specifically in the DP suggests it acts to regulate DP size during a critical period in follicular regeneration. We will test this hypothess with gain of function and rescue experiments and identify the gene expression changes that mediate Sox2 function in the DP. Signals within and between follicles, as well as from surrounding cell types in the skin all contribute to specifying DP size. To characterize those signals, we will extend our studies using DP specific blockade of additional signaling pathways to characterize how they contribute to these two mechanisms, signal production per DP cell and regulation of DP cell number. Successful completion of this work will provide insight into the mechanisms by which a progenitor pool interacts with and molds its niche and how that niche contributes to the regulation organ size and shape in the context of the changing needs of the organism. PUBLIC HEALTH RELEVANCE: The hair follicle is formed from adult stem cells under the influence of a second cell population, the dermal papilla, that directs these cells to form a hair f specific size and shape. By manipulating gene activity in the dermal papilla, we will identify the mechanisms by which the size of cell progenitor pools and their supporting niche populations are generated in the hair follicle, and how that dictates the size and shape of the hair. This research will have implications for the prevention of hair loss or restoration of defective hair follicles, and will also shed insight into the more general mechanisms that regulate organ size and shape.